In the previous funding period. Project 3 discovered that the steroid hormones estrogen (E2) and progesterone (P4) elicit a protective mechanism in CNS neurons representing a critical component of the reestablishment of the cytosolic free calcium ion homeostasis resulting in profound neuroprotection. Specifically, E2 and P4 as part of this mechanism are capable of changing the activity of intracellular calcium channels non-genomically through distinct kinase signaling pathways that induce specific post-translational modifications. However, a critical impediment to the full development of the neuroprotective potential of these hormones as pharmacotherapies is their limited therapeutic window and systemic side-effects. In particular, the use of steroid hormones to combat disease processes affecting neurons during aging and Alzheimer's disease (AD) is limited to a short time period after menopause in female individuals as shown by a number of seminal studies. In addition, usefulness is also extremely limited throughout the lifespan due to carcinogenic and estrogenic side-effects in male and postmenopausal female individuals. The present competitive renewal focuses on this mechanism and that improved neuronal viability is generated by steroid hormones controlling the state of specific PTMs of ICCs. Specifically, steroid hormone signaling induces these modifications and steroid hormone binding proteins functionally associated with ICCs modulate this activity. In particular, the time course and sustainability of neuroprotective PTMs will be measured for clinically relevant therapeutic windows; alternative therapeutic strategies will be determined to induce the same PTMs of ICC and thereby elicit neuroprotection. This strategy can bypass potential carcinogenic and estrogenic side-effects. This is of high significance because such effects of E2 and P4 on calcium signaling, data generated in the previous funding period, are potential clinically relevant cytoprotection strategies for age-related disorders affecting the nervous systems and neurodegenerative diseases including AD. When generated independently in clinically relevant penods, i.e. beyond the therapeutic window of steroid hormones themselves, such effects represent novel therapeutic approaches with high clinical relevance. The overall goal of the study is to identify the druggability of non-genomic actions of E2 and P4 in the CNS and of steroid hormone controlled calcium signaling proteins. This innovative strategy has a significant potential to expand the narrow therapeutic window for steroid mediated neuroprotection into an age range that is clinically relevant to achieve neuroprotection against processes underlying CNS aging and AD.